DESCRIPTION: (Applicant's Abstract) Cocaine abuse continues to be a significant public health problem. In spite of increased scientific investigation, the brain mechanisms responsible for compulsive cocaine use are still not clearly defined. Although dopamine has an important role, therapeutic approaches based on this premise have been disappointing. The basic brain processes underlying compulsive cocaine use involve complex neuronal circuits. This research project proposes continued investigation of these brain processes using a rat intravenous self-administration model. Microdialysis, neurotoxin lesions and intracranial administration of specific receptor agonists and antagonists will be used to further define the neuronal systems necessary for intravenous cocaine self-administration. Microdialysis will be used to evaluate the involvement of dopamine, GABA and glutamate innervations of several brain regions identified with neurotransmitter turnover rate measurements. Innervations that show specific changes in extracellular concentration will be further characterized with either intracranial neurotoxin lesions or specific receptor agonists or antagonists and assessing effects on drug intake. The specificity of observed effects from these treatments will be determined by assessing whether similar treatments alter food maintained responding. The experiments outlined in this application should further define the involvement of dopamine, GABA, glutamate, and ACh systems in the brain processes responsible for cocaine self-administration. Further understanding of these brain processes will hopefully lead to the development of more effective therapeutic approaches for individuals seeking to withdraw and abstain from compulsive cocaine use.